Effect of glucosylceramide on the biophysical properties of fluid membranes

Varela, Ana R.P.; Silva, Amélia M. Gonçalves da; Fedorov, Alexander; Futerman, Anthony H.; Prieto, Manuel; Silva, Liana C.

doi:10.1016/j.bbamem.2012.11.018

Cited by 34 publications

(43 citation statements)

References 77 publications

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“…This response could be a consequence of the increased tilt in the extracellular domain in the absence of GluCer but could also indicate that GluCer has a stabilizing effect on the transmembrane helices through modification of the membrane properties. In agreement with previous findings 31 , we showed that the presence of GluCer in the membrane increased the lipid order and therefore lipid packing, which could contribute to the stability of the helices and thereby to a reduction in the LPS-induced tilt of the TLR4 extracellular domain. Patra et al .…”

Section: Discussionsupporting

confidence: 93%

Glucosylceramide modifies the LPS-induced inflammatory response in macrophages and the orientation of the LPS/TLR4 complex in silico

Mobarak

Håversen

Manna

et al. 2018

Sci Rep

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Toll-like receptor 4 (TLR4) is activated by bacterial lipopolysaccharide (LPS), which drives the production of proinflammatory cytokines. Earlier studies have indicated that cholesterol- and glycosphingolipid-rich subregions of the plasma membrane (lipid domains) are important for TLR4-mediated signaling. We report that inhibition of glucosylceramide (GluCer) synthase, which resulted in decreased concentrations of the glycosphingolipid GluCer in lipid domains, reduced the LPS-induced inflammatory response in both mouse and human macrophages. Atomistic molecular dynamics simulations of the TLR4 dimer complex (with and without LPS in its MD-2 binding pockets) in membranes (in the presence and absence of GluCer) showed that: (1) LPS induced a tilted orientation of TLR4 and increased dimer integrity; (2) GluCer did not affect the integrity of the LPS/TLR4 dimer but reduced the LPS-induced tilt; and (3) GluCer increased electrostatic interactions between the membrane and the TLR4 extracellular domain, which could potentially modulate the tilt. We also showed that GCS inhibition reduced the interaction between TLR4 and the intracellular adaptor protein Mal. We conclude that the GluCer-induced effects on LPS/TLR4 orientation may influence the signaling capabilities of the LPS/TLR4 complex by affecting its interaction with downstream signaling proteins.

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Section: Discussionsupporting

confidence: 93%

Glucosylceramide modifies the LPS-induced inflammatory response in macrophages and the orientation of the LPS/TLR4 complex in silico

Mobarak

Håversen

Manna

et al. 2018

Sci Rep

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“…Using TLC, separate groups concluded that glycolipids might be involved in binding to tear lipocalins ( 18 ). It has been suggested that the lacrimal gland might be a probable source of such lipids and that the protein lipocalin might be secreted from the gland already fully charged with these lipids ( 20 ). Correspondingly, our results showed that GluCer is hydroperoxides ( 15 ).…”

Section: Study Groupsupporting

confidence: 72%

Lipidomic analysis of human tear fluid reveals structure-specific lipid alterations in dry eye syndrome

Lam

Tong

Reux

et al. 2014

Journal of Lipid Research

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Dry eye syndrome (DES) represents one of the most frequently encountered ocular morbidities, which can affect up to approximately one-third of the population worldwide depending on the criteria and defi nition used in the various studies conducted across the continents ( 1 ). Recent studies in China and Japan have, however, revealed a much higher prevalence than the average value reported globally ( 2, 3 ), indicating that Asian populations might have a greater predisposition to the disease. Despite its prevalence, there is presently no universal consensus on the diagnostic guidelines for the disease ( 4 ). Current clinical tests lack reproducibility and are not suffi ciently predictive of symptomatology to facilitate effective disease diagnosis and prognosis ( 5 ).The importance of tear lipids in maintaining ocular surface homeostasis and visual acuity due to their critical roles in constituting the outermost layer of the tear fi lm has been extensively reported and discussed ( 5-8 ). In particular, with the recent development in mass spectrometric technology, lipidomics has been transformed into a principal tool in biomedical research to decipher fi ne changes in lipid metabolism in various diseases including the DES ( 9, 10 ). Elucidating single tear components that are specifi cally altered with disease therefore marks the future of dry eye research by revealing novel molecular targets for improving current diagnostic and therapeutic platforms. Compared with tears, meibum-derived lipid markers indicative of DES Abstract As current diagnostic markers for dry eye syndrome (DES) are lacking in both sensitivity and specifi city, a pressing concern exists to develop activity markers that closely align with the principal axes of disease progression. In this study, a comprehensive lipidomic platform designated for analysis of the human tear lipidome was employed to characterize changes in tear lipid compositions from a cohort of 93 subjects of different clinical subgroups classifi ed based on the presence of dry eye symptoms and signs. Positive correlations were observed between the tear levels of cholesteryl sulfates and glycosphingolipids with physiological secretion of tears, which indicated the possible lacrimal (instead of meibomian) origin of these lipids. Notably, we found wax esters of low molecular masses and those containing saturated fatty acyl moieties were specifi cally reduced with disease and signifi cantly correlated with various DES clinical parameters such as ocular surface disease index, tear breakup time, and Schirmer's I test (i.e., both symptoms and signs). These structure-specifi c changes in tear components with DES could potentially serve as unifying indicators of disease symptoms and signs. In addition, the structurally-specifi c aberrations in tear lipids reported here were found in patients with or without aqueous deficiency, suggesting a common pathology for both DES subtypes.

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“…Receptor dimerization is affected by membrane lipid composition [35]. In GD, changes in lipid composition affect a number of biophysical properties of membranes [36], and we suggest that altered GlcCer levels may directly impinge upon, and perhaps stimulate PRR dimerization, thus activating the IFN response. Nevertheless, since this response can be eliminated with no effect on the lifespan, at least in nGD mice, activation of the IFN pathway may be unrelated to primary disease pathophysiology.…”

Section: Discussionmentioning

confidence: 87%

Mice defective in interferon signaling help distinguish between primary and secondary pathological pathways in a mouse model of neuronal forms of Gaucher disease

Vardi

Ben‐Dor

Cho

et al. 2020

J Neuroinflammation

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Background: The type 1 interferon (IFN) response is part of the innate immune response and best known for its role in viral and bacterial infection. However, this pathway is also induced in sterile inflammation such as that which occurs in a number of neurodegenerative diseases, including neuronopathic Gaucher disease (nGD), a lysosomal storage disorder (LSD) caused by mutations in GBA. Methods: Mice were injected with conduritol B-epoxide, an irreversible inhibitor of acid beta-glucosidase, the enzyme defective in nGD. MyTrMaSt null mice, where four adaptors of pathogen recognition receptors (PRRs) are deficient, were used to determine the role of the IFN pathway in nGD pathology. Activation of inflammatory and other pathways was analyzed by a variety of methods including RNAseq. Results: Elevation in the expression of PRRs associated with the IFN response was observed in CBE-injected mice. Ablation of upstream pathways leading to IFN production had no therapeutic benefit on the lifespan of nGD mice but attenuated neuroinflammation. Primary and secondary pathological pathways (i.e., those associated or not with mouse survival) were distinguished, and a set of~210 genes including those related to sphingolipid, cholesterol, and lipoprotein metabolism, along with a number of inflammatory pathways related to chemokines, TNF, TGF, complement, IL6, and damage-associated microglia were classified as primary pathological pathways, along with some lysosomal and neuronal genes. Conclusions: Although IFN signaling is the top elevated pathway in nGD, we demonstrate that this pathway is not related to mouse viability and is consequently defined as a secondary pathology pathway. By elimination, we defined a number of critical pathways that are directly related to brain pathology in nGD, which in addition to its usefulness in understanding pathophysiological mechanisms, may also pave the way for the development of novel therapeutic paradigms by targeting such pathways.

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Effect of glucosylceramide on the biophysical properties of fluid membranes

Cited by 34 publications

References 77 publications

Glucosylceramide modifies the LPS-induced inflammatory response in macrophages and the orientation of the LPS/TLR4 complex in silico

Glucosylceramide modifies the LPS-induced inflammatory response in macrophages and the orientation of the LPS/TLR4 complex in silico

Lipidomic analysis of human tear fluid reveals structure-specific lipid alterations in dry eye syndrome

Mice defective in interferon signaling help distinguish between primary and secondary pathological pathways in a mouse model of neuronal forms of Gaucher disease

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